The Use of Deferiprone to Improve Subarachnoid Hemorrhage Cognitive Outcome: U-DISCO

项目总结： 动脉瘤性蛛网膜下腔出血(ASAH)病死率高(~60%)，其中 幸存者在功能上变得依赖。ASAH幸存者有长期的认知和记忆缺陷 在他们的生产年龄段中受到损害，在工作和家庭方面负有主要责任。 在一项为期30年的全国性人群队列研究中，作者使用了丹麦医学数据库的数据 计算中风后30年内患痴呆症的绝对风险和危险比(HR)。与.相比 缺血性卒中幸存者患痴呆症的总体比例(95%可信区间)为 脑出血后1.72(1.66~1.77)，2.70(2.53~2.89)，ASAH后2.74(2.45~3.06)。 为什么会这样？？在ASAH受试者中，血红蛋白(Hb)和非血红素铁(Fe)的积累是 红血球的天然副产物裂解会导致大量神经细胞死亡。几项临床前研究 动物表明，这两种产品都会导致神经元死亡和接触它的任何大脑结构的萎缩。 特别是海马体和杏仁核。这些数据在人类身上复制，作者在那里发现， 脑脊液中铁蛋白(Ft)的水平被发现与脑组织中铁的含量密切相关。 进展为阿尔茨海默病(AD)。 这一过程的机制路径是什么？我们的研究小组表明，Hb对神经细胞有毒性 体外培养和加入去铁酮可显著减弱和逆转这一效应。然后我们确认了这些 结果造成小鼠脑室出血模型。此外，在一项概念验证研究中，我们展示了 De可显著降低脑脊液中Ft(p&lt；0.0001)，提示有潜在的治疗作用。此外， 其他研究也表明，在使用不同动物模型的临床前研究中，铁络合剂降低了铁 蛛网膜下腔和脑室内的内容物改善大鼠的功能和认知结局 这些动物。因此，我们提出这项拨款是为了验证去铁酮，一种脂溶性铁的假设。 螯合剂，因此容易扩散通过血脑屏障，将显著降低Ft(a 脑脊液中总非血红素铁含量的报告)，从而改善认知功能。 为了验证这一假设，我们提出了一项1/2a阶段的单中心随机双盲安慰剂与非安慰剂对照试验。 这招募了66名患有ASAH的受试者，这些受试者需要将EVD作为护理标准。科目 将被随机分为2组：A)安慰剂+B)15 mg/kg，每日2次，共21天。《金融时报》将按日收取 从脑脊液。我们还将使用蒙特利尔认知评估测试和一项 一系列标准化和广泛使用的认知测试，测量认知和 行为功能。我们还将评估该队列中海马体和杏仁体的体积 将他们与使用特定MRI方案的匹配的历史对照队列进行比较。这些测试将是相关的 用脑脊液中的Ft含量和脑成像上的海马体和杏仁核体积进行研究。

Project Summary: Aneurysmal subarachnoid hemorrhage (aSAH) has a high mortality rate (~60%), with a large proportion of the survivors becoming functionally dependent. aSAH survivors have long term cognitive deficits and memory impairment in their productive years with major responsibilities with respect to work and family. In a 30-year nationwide population-based cohort study using data from Danish medical databases, the authors computed the absolute risks and hazard ratios (HR) of dementia up to 30 years after stroke. Compared with the general population, the HR (95% confidence interval) for dementia among ischemic stroke survivors was 1.72 (1.66–1.77), 2.70 (2.53–2.89) after intracerebral hemorrhage, and 2.74 (2.45–3.06) after aSAH. Why is that?? In aSAH subjects, accumulation of hemoglobulin (Hb) and non-heme iron (Fe) which are the natural byproduct lysis of red blood cells leads to significant neuronal cells death. Several preclinical studies in animals showed that both products lead to neuronal death and atrophy of any brain structures exposed to it and specifically the hippocampus and amygdala. These data were replicated in human, where authors found, the level of ferritin (Ft) in CSF, a reporter of the amount of Fe in brain, was found to strongly correlate with progression to Alzheimer's disease (AD). What is the mechanistic pathway of this process?? Our group showed that Hb is toxic to neuronal cells in vitro and adding deferiprone (De) attenuated and reversed this effect significantly. We then confirmed these results in a mouse model of intraventricular hemorrhage. Additionally, in a proof-of-concept study we showed that De significantly decreased Ft in CSF (p<0.0001) suggesting a potential therapeutic effect. Furthermore, others also showed in preclinical studies using different animal models, Fe chelating agents decrease Fe content both in the subarachnoid space and intraventricular improving the functional and cognitive outcome in these animals. Therefore, we propose this grant to test the hypothesis that deferiprone, a lipid soluble Fe chelating agent and therefore diffuse easily across the blood-brain barrier, will significantly decrease Ft (a reporter of total non-heme Fe content in CSF) in subjects with aSAH and hence improve cognitive function. To test this hypothesis, we propose a phase 1/2a single-center randomized double-blinded placebo vs. De trial that recruits and enrolls 66 subjects with aSAH who require placement of EVD as a standard of care. Subjects will be randomized equally into 2 groups: A) placebo & B) 15 mg/kg bid for 21 days. Ft will be collected daily from CSF. We will also test the cognitive changes using the Montreal Cognitive Assessment test along with a battery of well-standardized and widely used cognitive tests that measure various aspects of cognitive and behavioral functioning. We will also assess the volume of hippocampus and amygdala in this cohort and compare them to a matched, historic control cohort using specific MRI protocol. These tests will be correlated with the Ft content in CSF and the volume of hippocampus and amygdala on imaging studies obtained.